Mayo-Clinic-Led Team Develops 77-SNP-Based Risk Factor Score to Identify Women at Increased Risk of Breast Cancer

Recent large-scale genomic analyses have uncovered dozens of common genetic variants that are associated with breast cancer. Each variant, however, contributes only a tiny amount to a person’s overall risk of developing the disease. A Mayo Clinic-led team of international researchers has now combined 77 of these common genetic variants into a single risk factor that can be used to improve the identification of women with an elevated risk of breast cancer. This factor, known as a polygenic risk score, was built from the genetic data of more than 67,000 women. The results of the research were published online on April 2, 2015, in the Journal of the National Cancer Institute (JNCI). A companion study has extended this finding to show that this measure of genetic variation can be combined with traditional predictors of breast cancer risk such as breast density and family history to improve personalized estimates of breast cancer risk. These latter findings appeared in JNCI last month. “This genetic risk factor adds valuable information to what we already know can affect a woman’s chances of developing breast cancer,” says study co-author Celine Vachon, Ph.D., an epidemiologist at the Mayo Clinic. “We are currently developing a test based on these results, and though it isn’t ready for clinical use yet, I think that within the next few years we will be using this approach for better personalized screening and prevention strategies for our patients.” Scientists have known for decades that genetics can play a role in breast cancer. For example, inheriting a mutation in BRCA1 or BRCA2 genes greatly increase a woman’s risk of developing the disease, but these mutations are rare and account for less than five percent of all breast cancers.

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UCSF Team Finds Lung Cancer Tumor That Activates NF-Kappa-B Pathway to Resist Effects of EGFR-Targeted Drugs Like Erlotinib; Experimental Drug Exists to Block NF-Kappa-B Pathway and, If Used with Erlotinib, Might Prove Highly Effective

Capitalizing on a rare opportunity to thoroughly analyze a tumor from a lung cancer patient who had developed resistance to targeted drug treatment, UC-San Francisco (UCSF) scientists identified a biological escape hatch that explains the resistance, and developed a strategy in mice for shutting it down. In experiments that combined the drug the patient had taken with a second compound that blocks off this newly discovered resistance pathway, the researchers were able to durably wipe out cancer cells in mice implanted with cells from the drug-resistant human tumor. “Even in cancers that are responding to targeted therapy by conventional criteria, resistance is already developing,” said the senior author of the new study, Trever Bivona, M.D., Ph.D., Assistant Professor of Medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “In this work we have begun to crack open the question of why residual disease persists after targeted therapy.” Between 10 and 35 percent of non-small cell lung cancer (NSCLC) patients carry mutations in a gene that codes for a cell-surface protein called the epidermal growth factor receptor (EGFR). As its name suggests, under normal circumstances, when a growth factor protein locks onto the EGFR, the receptor sends signals that prompt cells to divide and proliferate. But the EGFR mutations seen in NSCLC cause the receptor to be stuck in an “on” position, leading to rampant cell proliferation. Over the past decade, medications such as erlotinib (trade name Tarceva), which precisely targets the EGFR and tamps down its activity, have advanced the treatment of EFGR-mutant NSCLC beyond chemotherapy, but significant challenges remain.

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Certain Archaea Freeze in Place and Go Dormant When Confronted by Viruses

The microbes could surrender to the harmless virus, but instead they freeze in place, dormant, waiting for their potential predator to go away, according to a study published online on March 31, 2015 in mBio. The article is entitled “Virus-Induced Dormancy in Archaeon Sulfolobus islandicus.” University of Illinois researchers found that Sulfolobus islandicus organisms can go dormant, ceasing to grow and reproduce, in order to protect themselves from infection by Sulfolobus spindle-shaped virus 9 (SSV9). The dormant microbes are able to recover if the virus goes away within 24 to 48 hours–otherwise they die. “The microbe is hedging its bet,” said Associate Professor of Microbiology Rachel Whitaker, who led the research at the Carl R. Woese Institute for Genomic Biology. “If they go dormant, they might die, but we think this must be better than getting infected and passing it on.” Sulfolobus islandicus is a species of archaea (a domain of single-celled organisms distinct from bacteria) found in acidic hot springs (photo) all over the world, where free viruses are not as common as in other environments. These microbes will go dormant in the presence of just a few viruses, whether active or inactive. While inactivated virus particles cannot infect a host, Dr. Whitaker’s lab found they could still cause dormancy, and ultimately, death in Sulfolobus islandicus. “People thought these inactivated viruses were just an accident, that they were just mispackaged,” Dr. Whitaker said. “Now we know they are being sensed by the host so they are having an effect.

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Single-Cell Analysis Used to Illuminate Acute Myeloid Leukemia (AML); Staggering Genetic Diversity Revealed; May Dictate Change of Approach for Battling This Type of Cancer

All living things–from dandelions to reindeer–evolve over time. Cancer cells are no exception, and are subject to the two overarching mechanisms described by Charles Darwin: chance mutation and natural selection. In new research, Carlo Maley, Ph.D., and his colleagues describe compulsive evolution and dramatic genetic diversity in cells belonging to one of the most treatment-resistant and lethal forms of blood cancer: acute myeloid leukemia (AML). The authors suggest the research may point to new paradigms in both the diagnosis and treatment of aggressive cancers, like AML. Dr. Maley is a researcher at Arizona State University’s (ASU’s) Biodesign Institute and an Assistant Professor in ASU’s School of Life Sciences. His work focuses on applying principles of evolutionary biology and ecology to the study of cancer. The group’s latest findings [the group included collaborators from Fred Hutchinson Cancer Research Center, the University of Pennsylvania, and UCSF] were published online on April 1, 2015 in Science Translational Medicine. The article is titled “Single-Cell Genotyping Demonstrates Complex Clonal Diversity in Acute Myeloid Leukemia.” A tumor is a laboratory for evolutionary processes in which nature experiments with an immense repertoire of variants. Mutations that improve a cell’s odds of survival are “selected for,” while non-adaptive cells are weeded out in the evolutionary lottery. Genetic diversity therefore provides cancer cells with a library of possibilities, with some mutations conferring heightened resistance to attack by the body’s immune system and others helping malignant cells foil treatments like chemotherapy. Generally speaking, the seriousness of a given cancer diagnosis may be linked with genetic diversity in cancerous cells.

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CHOP Using Ultra-Small, Specially Formulated Nanoparticles to Target Neuroblastomas with High-Payload Drug Delivery; Animal Model Success Suggests Clinical Trials May Start within Next Year

Delving into the world of the extremely small, researchers are exploring how biodegradable nanoparticles can precisely deliver anticancer drugs to attack neuroblastoma, an often-deadly children’s cancer. By bringing together experts in pediatric oncology with experts in nanotechnology, researchers at The Children’s Hospital of Philadelphia (CHOP) aim to thread the needle of delivering effective doses of cancer-killing agents while avoiding toxicity in healthy tissues. The team’s new research shows that this approach inhibits tumor growth and markedly prolongs survival in animal models. “These nanoparticles allow us to get more ‘bang for the buck’–greater efficacy at lower total doses,” said Garrett M. Brodeur, M.D., a pediatric oncologist and expert in neuroblastoma at CHOP. “The nanoparticles are designed to slowly deliver a drug to the tumor, where it kills multiplying cancer cells, with lower toxicity to the systemic circulation.” Dr. Brodeur’s group collaborated with a group of CHOP nanotechnology researchers led by Michael Chorny, Ph.D., in a study to be published in print May 1, 2015 in Cancer Letters. The Cancer Letters article was published online on February 12, 2015, and is titled “Nanoparticle Delivery of an SN38 Conjugate Is More Effective Than Irinotecan in a Mouse Model of Neuroblastoma.” Dr. Chorny, in turn, led a study to be published in the May print issue of Biomaterials, in collaboration with Brodeur’s group and with Robert Levy, M.D., and Ivan Alferiev, Ph.D., both members with Dr. Chorny of a cardiology research group at CHOP. That paper, which described how the team engineered the specially formulated nanoparticles, was published online on February 16, 2015, and is titled “”Nanoparticle-Mediated Delivery of a Rapidly Activatable Prodrug of SN-38 for Neuroblastoma Therapy.” This approach, explained Dr.

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UCSF-Led Study Suggests Superiority of Non-Invasive, Cell-Free DNA Blood Test in Detecting Down Syndrome; Test Not As Widely Comprehensive for Other Ailments As Standard Tests, However

A blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicenter study led by a University of Californian, San Francisco (UCSF) researcher. In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 fetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal, or postnatal genetic analysis. The test focuses on the small percentage of fetal DNA found floating in a pregnant woman’s blood. DNA is amplified with a molecular “photocopying” technique known as polymerase chain reaction (PCR), and sequenced so that comparisons can be made between relative amounts of each chromosome’s DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes. When the same women underwent standard screening, 30 of the 38 fetuses with Down syndrome were flagged, according to the study published online on April 1, 2015, in the New England Journal of Medicine. The article title is “Cell-Free DNA Analysis for Noninvasive Examination of Trisomy.” The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.

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Scientists Achieve Small Molecule Inhibition of Aberrant Transcription Factor at Root of Recurring Acute Myeloid Leukemia (AML)

A novel molecule designed by scientists at the University of Massachusetts Medical School and the University of Virginia inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia (AML) in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor. Previously thought to be an undruggable target, this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors. Details of the work were published in the February 13, 2015 issue of Science. The article is titled “A Small-Molecule Inhibitor of the Aberrant Transcription Factor CBFβ-SMMHC Delays Leukemia in Mice.” Transcription factors are single- or multi-protein complexes that regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome next to a gene. Mutations in transcription factors can result in altered gene expression programs that give way to new, cancer-causing functions. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has made it difficult to find small molecules or design drugs that treat these transcription factor-related cancers. “When we look at inhibitors, they usually target an enzyme or receptor. There aren’t a lot of good examples of transcription factor inhibitors in clinical trials,” said Lucio H. Castilla, Ph.D., Associate Professor of Molecular, Cell, and Cancer Biology at the U-Mass Medical School, and co-leader of the study. “Here, we’ve used our extensive knowledge of a mutant transcription factor found in a subset for acute myeloid leukemia patients to design a molecule that can specifically sequester only the oncogenic mutant.

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Synchronization of Womb’s and Mother’s Biological Clocks Plays Key Role in Successful Pregnancies

If you are trying to have a baby, a good night’s sleep is more important than ever. A new research report appearing in April 2015 issue of The FASEB Journal shows that the womb has its own “body clock” that needs to synchronize with the mother’s body clock to ensure optimal conditions for fetal growth and development. The inability of a mother’s body clock to synchronize with the womb’s clock may be at least part of the reason why some women have difficulty carrying a pregnancy to full term. Specifically, the failed synchronization switches off body clock genes in cells lining the womb, which in turn, may jeopardize the pregnancy. This information may help researchers and fertility experts develop strategies to optimize the fetal environment to help more women have children. “Infertility affects one in six couples across the world. Miscarriage is the most common complication of pregnancy,” said Jan Brosens, M.D., a researcher involved in the work from the Division of Translational and Systems Medicine and Reproductive Health at Warwick Medical School at the University of Warwick in Coventry, UK. “Approximately one in seven clinical pregnancies result in miscarriage, mostly prior to 12 weeks of pregnancy. It is estimated that five percent of women experience two clinical miscarriages and approximately one percent have three or more losses. From a medical perspective, recurrent miscarriages and implantation failure have remained frustratingly devoid of effective therapeutic strategies.” To make the current discovery, Dr. Brosens and colleagues, obtained womb biopsies from 70 women who have experienced recurrent pregnancy loss. The cells from these biopsies were purified and then treated in such a way as to simulate a pregnancy.

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Shorter and Still Effective Cas9 Enzyme from S. aureus Enables Easier Packaging into AAV Delivery Vehicle; Nobelist Sharp Is One of Study Leaders

A collaborative study among researchers from the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, and the National Center for Biotechnology Information of the National Institutes of Health (NIH-NCBI) has identified a highly efficient Cas9 nuclease that overcomes one of the primary challenges to in vivo genome editing. This finding, published online on April 1, 2015 in Nature, is expected to help make the CRISPR toolbox accessible for in vivo experimental and therapeutic applications. Originally discovered in bacteria, the CRISPR-Cas9 system enables the cutting of DNA as a defense mechanism against viral infection. Although numerous microbial species possess this system, the Cas9 enzyme from Streptococcus pyogenes (SpCas9) was the first to be engineered for altering the DNA of higher organisms, and has since emerged as the basis for a series of highly versatile genome modification technologies. In order to perturb genes in adult animals, key components of the CRISPR-Cas9 system must be introduced into cells using delivery vehicles known as vectors. Adeno-associated virus (AAV) is considered one of the most promising candidate vectors, as it is not known to cause human disease and has already gained clinical regulatory approval in Europe. However, the small cargo capacity of AAV makes it challenging to package both the SpCas9 enzyme and the other components required for gene editing into a single viral particle. The Cas9 nuclease from the bacteria Staphylococcus aureus (SaCas9), presented in this new work, is 25% smaller than SpCas9, offering a solution to the AAV packaging problem. The Broad/MIT team, led by Dr. Feng Zhang, core member of the Broad Institute and investigator at the McGovern Institute for Brain Research at MIT, along with collaborators at MIT, led by MIT Institute Professor Dr.

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NO APRIL FOOL’S: Tiny Blackpoll Warbler Migrates 1,500 Miles in Non-Stop “Fly-or-Die” Journey Over Atlantic Ocean in 2-3 Days; “One of the Most Extraordinary Migratory Routes on the Planet” Expert Says

For more than 50 years, scientists had tantalizing clues suggesting that a tiny, boreal forest songbird known as the blackpoll warbler departs each fall from New England and eastern Canada to migrate nonstop in a direct line over the Atlantic Ocean toward South America, but proof was hard to come by. Now, for the first time, an international team of biologists report “irrefutable evidence” that the birds complete a nonstop flight ranging from about 1,410 to 1,721 miles (2,270 to 2,770 km) in just two to three days, making landfall somewhere in Puerto Rico, Cuba and the islands known as the Greater Antilles, from there going on to northern Venezuela and Columbia. Details of the new study, which used light-level, or solar, geolocators, were published online on April 1, 2015 in Biology Letters. First author Dr. Bill DeLuca, an Environmental Conservation Research Fellow at the University of Massachusetts Amherst, with colleagues at the University of Guelph, Ontario, the Vermont Center for Ecostudies, and other institutions, says, “For small songbirds, we are only just now beginning to understand the migratory routes that connect temperate breeding grounds to tropical wintering areas. We’re really excited to report that this is one of the longest nonstop overwater flights ever recorded for a songbird, and finally confirms what has long been believed to be one of the most extraordinary migratory feats on the planet.”While other birds, such as albatrosses, sandpipers, and gulls are known for trans-oceanic flights, the blackpoll warbler is a forest dweller that migrates boldly where few of its relatives dare to travel. Most migratory songbirds that winter in South America take a less risky, continental route south through Mexico and Central America, the authors note. A water landing would be fatal to a warbler.

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